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J. Biol. Chem., Vol. 281, Issue 33, 23740-23747, August 18, 2006

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The KCNE2 Potassium Channel Ancillary Subunit Is Essential for Gastric Acid Secretion^*

Torsten K. Roepke, Arun Anantharam^¶, Philipp Kirchhoff^||**, Stephanie M. Busque^**, Jeffrey B. Young, John P. Geibel^||**, Daniel J. Lerner, and Geoffrey W. Abbott¹

From the Greenberg Division of Cardiology, Department of Medicine, Department of Pharmacology, and ^¶Neuroscience Graduate Program, Cornell University, Weill Medical College, New York, New York 10021, Departments of ^||Surgery and ^**Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, and FoxHollow Technologies, Redwood City, California 94063

Genes in the KCNE family encode single transmembrane domain ancillary subunits that co-assemble with voltage-gated potassium (Kv) channel subunits to alter their function. KCNE2 (also known as MiRP1) is expressed in the heart, is associated with human cardiac arrhythmia, and modulates cardiac Kv subunits hERG and KCNQ1 in vitro. KCNE2 and KCNQ1 are also expressed in parietal cells, leading to speculation they form a native channel complex there. Here, we disrupted the murine kcne2 gene and found that kcne2 (-/-) mice have a severe gastric phenotype with profoundly reduced parietal cell proton secretion, abnormal parietal cell morphology, achlorhydria, hypergastrinemia, and striking gastric glandular hyperplasia arising from an increase in the number of non-acid secretory cells. KCNQ1 exhibited abnormal distribution in gastric glands from kcne2 (-/-) mice, with increased expression in non-acid secretory cells. Parietal cells from kcne2 (+/-) mice exhibited normal architecture but reduced proton secretion, and kcne2 (+/-) mice were hypochlorhydric, indicating a gene-dose effect and a primary defect in gastric acid secretion. These data demonstrate that KCNE2 is essential for gastric acid secretion, the first genetic evidence that a member of the KCNE gene family is required for normal gastrointestinal function.

Received for publication, May 1, 2006 , and in revised form, May 31, 2006.

^* This work was supported by American Heart Association Grant 0235069N (to G. W. A.), National Institutes of Health Grants R01 HL079275 and RO3 DC07060 (to G. W. A.) and R01 DK50230 (to J. G.), and Swiss National Science Foundation Grant PBZHB-110427 (to P. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Starr 463, Greenberg Division of Cardiology, Weill Medical College of Cornell University, 520 E. 70th St., New York, NY 10021. Tel.: 212-746-6275; Fax: 212-746-7984; E-mail: gwa2001{at}med.cornell.edu.

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